The introduction of HIV antiretroviral medication (ARVs) in Africa have resulted in substantial reductions in morbidity and mortality, and in related social benefits. However, programs will encounter many challenges, some of which are similar to those observed in North America (such as behavioral disinhibition), and some of which differ (including the availability of a limited range of ARV regimens, widespread use of nevirapine for prevention of mother-to-child HIV transmission, and the presence of non-B HIV subtypes). We have a narrow window of opportunity to examine the complex biological, epidemiological, behavioral and social effects of ARV programs as they are initiated in the region. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, the impact of immunologic monitoring and potential delays in detecting virologic failure on genotypic antiretroviral resistance, and the role of suppressive acyclovir therapy in HSV-2/HIV-1 co-infected individuals on HIV-1 disease progression and time to initiation of ARVs. As of June, 2004, the Rakai Program began ARV provision through the Presidents Emergency Program for AIDS Relief (PEPFAR). Because of Rakai's clinical, laboratory and community-based infrastructure, and the wealth of information available on the general population prior to the initiation of ARVs, the Rakai Program provides a unique opportunity to examine a broad range of ARV effects in a rural African setting. Referred to as the International Center for Excellence in Research (ICER), we are currently evaluating the impact of ARVs on HIV incidence among HIV discordant couples. The HIV incidence among HIV discordant couples enrolled in the Rakai Community Cohort Study between 2004 and 2008 was 8.5/100 person years. Despite similar risk behavior profiles, no HIV transmissions have occurred among 26 HIV discordant couples followed since the introduction of ARVs. The utility of immunologic monitoring of ARVs compared to virologic monitoring and the impact of delayed switching of therapy on the evolution of antiviral resistance is also being examined both at the Infectious Diseases Institute in Kampala and in the Rakai Program. We are specifically examining whether prolonged, undetected periods of virologic failure due to immunologic monitoring will result in a greater accumulation of thymidine analogue mutations (TAMS) in this non-clade B setting. An analysis comparing WHO immunologic failure/switch criteria to virologic monitoring among 1185 Rakai program participants on ARVs for at least 6 months revealed that the majority (>75%) of individuals with virologic failure would not have been identified using the WHO immunologic failure criteria despite a median follow-up time of 20 months. We are investigating other laboratory parameters, specifically MCV and MCH which may identify individuals who are non-adherent to ART and at risk for virologic failure. Interventions that slow HIV-1 disease progression among persons with CD4+ counts above 250 cells/L could postpone the need for antiretroviral therapy (ART) and prolong life-expectancy for HIV-infected persons. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We have previously published data from Rakai showing that individuals who are HSV-2 seropositive at the time of HIV-1 seroconversion had higher HIV viral loads at 5 and 15 months post-seroconversion. The potential of acyclovir to slow HIV-1 disease progression was recently shown in the partners in prevention study which observed a 17% reduction in progression to CD4<250 among HIV infected individuals treated with acyclovir 400mg twice daily. We are currently conducting a double blind placebo controlled trial to assess the benefits of acyclovir prophylaxis among HIV-1 infected individuals dually infected with HSV-2 who are not on ART to examine the impact of HSV-2 suppression on HIV-1 disease progression.